These are some of the oldest questions in developmental biology - and new research is beginning to provide fresh answers.
For decades, the classical textbook model proposed that a simple concentration gradient of a single protein - Sonic hedgehog (Shh) - was the sole mechanism. Meaning the protein spreads from one source, creating a signal that weakens as it travels, which determines the position and type of each digit.
But recent research from the team, led by Dr Matt Towers, in mouse models has shown that this explanation alone does not account for how mammals form five digits, leaving a gap in understanding how this process evolved.
To address this, researchers analysed the legs of chicks, which naturally have four digits. They engineered a five-digit leg structure by experimentally flattening the Shh concentration gradient, effectively creating a signal that stays the same strength as it travels.
This result directly challenged the classical view and suggests that digit patterning mechanisms diverged between mammalian and avian lineages over evolutionary time.
This new project, funded by the Biotechnology and Biological Sciences Research Council (BBSRC), will now explore this model further by manipulating a specific pathway: Shh-Bmp2-p27Kip1. Using their engineered pentadactyl model (five-digit), the team will manipulate this pathway to understand precisely how it controls digit number and identity.
The ultimate goal is to generate a unified framework for understanding digit patterns across all vertebrates, replacing the currently disparate approaches across species.
This fundamental scientific research has implications beyond basic developmental biology. The research is expected to offer new clues into the origins of human limb malformations and birth defects, with potential future applications in regenerative medicine and tissue engineering.
Dr Matt Towers